The toxic side effects of chemotherapy and debilitation caused by radical surgery have prompted the search for homeostatic alternatives to conventional cancer therapeutic modalities. In view of the many similarities between embryonic development and neoplasia, one area of promise in this search is the possibility that the malignant behavior of cells can be regulated by epigenetic mechanisms as are the cells of the embryo. More specifically, when competent malignant cells are placed in an appropriate microenvironment or individuation field they may pursue a normal developmental course and become benign. This proposal outlines the rationale and methods to explore this possibility by using the morphogenetic properties of demineralized diaphyseal bone matrix to effect the growth and differentiation of neoplastic cells. We have previously shown that the Swarm rat chondrosarcoma is induced by the microenvironment of bone morphogenesis to undergo a series of phenotypic changes which resemble terminal chondrocyte differentiation. We will determine the mechanisms through which this occurs by examining intracellular and extracellular markers of chondrocytic differentiation. The former include ultrastructure, clacium binding sites and enzyme histochemistry. The latter utilizes monoclonal antibodies against extracellular matrix components to examine qualitative and/or quantitative changes. A number of other sarcomas and continuous cell lines will also be evaluated for their ability to respond to morphogenetic induction. The specific aspects to be evaluated include in vivo modulation of tumor growth, tumor stem cell pluripotentiality, histogenetic specificity, developmental vs. nonspecific growth regulation and mesenchymal competence. In addition, we will continue to develop an in vitro model in an attempt to elucidate the specific molecular natures of the inductors operative in the bone matrix/tumor cell interaction. In so doing, we hope to provide both fundamental insight into the mechanisms of naturally occurring neoplasms and a clinically applicable method for the treatment of mesenchymal cancer.